Human antigen-specific T cell responses in viral control and immunopathology

The main objective of my group is to investigate the functional aspects of antigen specific cytotoxic T cells (CTL) with a focus on the factors affecting CTL in controlling virus infection and cancer progression.While a robust and appropriate T cell response is typically beneficial to the host during human infections, a weak or inappropriate response can be ineffective or even have a detrimental effect. Over the past two decades, our efforts have been on understanding the key factors required for efficient viral control by T cells in a number of different viral infections and cancer. To do this, we have established an ex-vivo and in-vitro T cell functional evaluation platforms for antigen-specific T cells isolated from tissue and blood. By linking these functional data with multi-omic single cell and T cell receptor (TCR) repertoire analysis, we have identified potential targets and pathways to augment and control the immune response as a way of improving the outcome of several important human diseases including SARS-CoV-2 virus infection.
In this proposal, we will address fundamental questions in CTL memory induction, central memory establishment and maintenance following virus infection and vaccination, with a particular focus on tissue-resident memory cells using SARS-CoV-2 as the model system. We aim to establish CTL functional relevance to efficient viral control and potential detrimental immunopathology in affected organs. By studying the immunology of tissues, we will provide scientific evidence and tools for improved vaccine design and therapeutic approaches for virus infections.

Over the past two years, we have established a biobank of samples collected following acute SARS-CoV-2 infection or a full cycle of vaccination. We have established an experimental system to comprehensively evaluate the broad range of SARS-CoV-2-specific T cell functionalities, in association with viral control and protection as well as potential pathogenesis. Detailed T cell responses, including mapping of immunodominant epitopes in each study subject post-infection and/or vaccination, and generation of autologous B cell lines as targets for future functional evaluation of T cell memory has been established (Peng et al, Nature Immunology 2022). In parallel, we established a system to evaluate T cell responses in detail by combining single cell transcriptome and TCR repertoire analysis of tetramer- or cytokine-sorted T cells with in-vitro functional evaluation and proteomic analysis of matched-TCR T cell clones. Functional analysis of T cells includes the evaluation of anti-viral efficacy and ability to control viral replication using live virus-infected autologous target cells. In the next five years, we will address fundamental unanswered questions on human immune memory T cell generation and maintenance post-infection and -vaccination, using SARS-CoV-2 human infection as a model. We will fill the current knowledge gap in understanding the evolution of T cell memory post infection/vaccination and the implications for virus re-infection, through testing the hypothesis that induction, maintenance and functional relevance of T cell immune memory following natural SARS-CoV-2 infection helps control viral replication but risks immunopathology. Data generated would provide the scientific foundation to explore novel avenues for potential preventative and therapeutic opportunities.